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The Journal of Steroid Biochemistry and... Jul 2014In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone... (Review)
Review
In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone loss, however there was no fracture data, even though it was thought to be effective. This continued until the Women's Health Initiative (WHI) study in 2001 that published data on 6 years of treatment with hormone therapy that showed an increase in heart attacks and breast cancer. Even though the risks were small, 1 per 1500 users annually, patients were worried and there was a large drop off in estrogen use. In later analyses the WHI study showed that estrogen reduced fractures and actually prevented heart attacks in the 50-60 year age group. Estrogen alone appeared to be safer to use than estrogen+the progestin medroxyprogesterone acetate and actually reduced breast cancer. At the same time other drugs were being developed for bone that belong to the bisphosphonate group and the first generation of compounds showed moderate potency on bone resorption. The second and third generation compounds were much more potent and in a series of large trials were shown to reduce fractures. For the last 15 years the treatment of osteoporosis belonged to the bisphosphonate compounds, most of which reduce fracture rates by 50 percent. With the exception of gastrointestinal irritation the drugs are well tolerated and highly effective. The sophistication of the delivery systems now allow treatment that can be given daily, weekly, monthly and annually either orally or intravenously. Bone remodeling is a dynamic process that repairs microfractures and replaces old bone with new bone. In the last 10 years there has been a remarkable understanding of bone biology so that new therapies can be specifically designed on a biological basis. The realization that RANKL was the final cytokine involved in the resorption process and that marrow cells produced a natural antagonist called Osteoprotegerin (OPG) quickly led to two lines of therapy. First OPG was used as a therapy to block RANKL was initially successful but later antibodies against OPG developed and this line of treatment had to be discontinued. The next step was to develop a monoclonal antibody against RANKL and this proved to be highly effective in blocking bone resorption. It led to development of a drug Denosumab that successfully reduces fractures and is now one of the therapeutic options for osteoporosis treatment. On the anabolic side bone biology research showed that osteocytes produces sclerostin an inhibitor of the anabolic WNT signaling pathway. Recent development of a monoclonal antibody against sclerostin has shown remarkable anabolic activity in bone showing large increases in bone density and fracture trials are now underway. The newer treatments for osteoporosis are likely to be based on our understanding of bone biology and the design of new highly specific compounds with fewer side effects. This review summarizes the diagnosis of postmenopausal osteoporosis and various available non-pharmacological and pharmacological therapies available for its management. This article is part of a Special Issue entitled 'Menopause'.
Topics: Aged; Aged, 80 and over; Alendronate; Antibodies, Monoclonal, Humanized; Bone Density; Bone Remodeling; Calcitonin; Denosumab; Diphosphonates; Estrogen Replacement Therapy; Female; Fractures, Bone; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Risk Factors; Selective Estrogen Receptor Modulators; Teriparatide
PubMed: 24176761
DOI: 10.1016/j.jsbmb.2013.09.008 -
International Journal of Cardiology Nov 2023The relationship between circulating osteoprotegerin (OPG) levels and the risk of cardiovascular diseases (CVDs) has been the subject of conflicting results in previous...
PURPOSE
The relationship between circulating osteoprotegerin (OPG) levels and the risk of cardiovascular diseases (CVDs) has been the subject of conflicting results in previous observational and experimental studies. To assess the causal effect of genetically predicted OPG levels on the risk of a wide range of CVDs, we used the Mendelian randomization design.
DESIGN
We initially extracted information of genetic variants on OPG levels and their corresponding effect values from the summary data based on the European ancestry genome-wide association study. Subsequently, we performed two-sample Mendelian randomization analyses to assess the causal effect of genetically predicted OPG levels on CVDs by using inverse variance weighting (IVW), MR-Egger, weighted median, and MR-PRESSO methods. We also conducted sensitivity analyzes as well as complementary analyses with a more relaxed threshold for the exposure genetic instrumental variable (P < 5 × 10) to test the robustness of our results.
RESULTS
Our results indicated that genetically predicted OPG levels causally reduce the risk of atrial fibrillation (IVW OR = 0.84; 95% CI = 0.72-0.98; P = 0.0241), myocardial infarction(IVW OR = 0.89; 95% CI = 0.80-0.98; P = 0.0173) and coronary heart disease (IVW: OR = 0.90; 95% CI = 0.82-0.99; P = 0.0286). Further complementary analyses also confirmed the above results remain robust and we also identified a potential causal association of OPG levels with a reduced risk of hypertensive diseases(IVW OR = 0.94;95% CI = 0.88-1.00; P = 0.0394).
CONCLUSION
This study provides compelling evidence for a causal relationship between genetically predicted OPG levels and risk reduction of coronary heart disease, myocardial infarction, and atrial fibrillation, indicating that OPG could potentially serve as a cardiovascular risk marker in clinical practice.
Topics: Humans; Atrial Fibrillation; Cardiovascular Diseases; Genome-Wide Association Study; Mendelian Randomization Analysis; Myocardial Infarction; Osteoprotegerin
PubMed: 37532154
DOI: 10.1016/j.ijcard.2023.131233 -
Journal of the American Heart... Apr 2022Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular...
Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher (<0.0001 by log-rank test) in 8-week-old male homozygotes of osteoprotegerin gene-knockout mice given subcutaneous administration of Ang II for 28 days, with an incidence of 21% fatal aortic rupture and 23% aortic dissection, than in age-matched wild-type mice. Ang II-infused aorta of wild-type mice showed that osteoprotegerin immunoreactivity was present with proteoglycan. The absence of osteoprotegerin was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with increased periostin expression and soluble receptor activator of nuclear factor-kappa B ligand concentrations. PEGylated human recombinant osteoprotegerin administration decreased all-cause mortality (<0.001 by log-rank test), the incidence of fatal aortic rupture (=0.08), and aortic dissection (<0.001) with decreasing numbers of elastin breaks, periostin expressions, and soluble receptor activator of nuclear factor-kappa B ligand concentrations in Ang II-infused osteoprotegerin gene-knockout mice. Conclusions These data suggest that osteoprotegerin protects against aortic rupture and dissection in Ang II-induced hypertension by inhibiting receptor activator of nuclear factor-kappa B ligand activity and periostin expression.
Topics: Aortic Dissection; Angiotensin II; Animals; Aortic Rupture; Disease Models, Animal; Elastin; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoprotegerin; RANK Ligand
PubMed: 35411794
DOI: 10.1161/JAHA.122.025336 -
Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(-/-) mice.Circulation Jan 2008The role of osteoprotegerin in vascular disease is unclear. Recent observational studies show that serum osteoprotegerin levels are associated with the severity and...
BACKGROUND
The role of osteoprotegerin in vascular disease is unclear. Recent observational studies show that serum osteoprotegerin levels are associated with the severity and progression of coronary artery disease, atherosclerosis, and vascular calcification in patients. However, genetic and treatment studies in mice suggest that osteoprotegerin may protect against vascular calcification.
METHODS AND RESULTS
To test whether osteoprotegerin induces or prevents vascular disease, we treated atherogenic diet-fed ldlr(-/-) mice with recombinant osteoprotegerin (Fc-OPG) or vehicle for 5 months. Vehicle-treated mice developed significant, progressive atherosclerosis with increased plasma osteoprotegerin levels, consistent with observational studies, and approximately 15% of these atherosclerotic lesions developed calcified cartilage-like metaplasia. Treatment with Fc-OPG significantly reduced the calcified lesion area without affecting atherosclerotic lesion size or number, vascular cytokines, or plasma cholesterol levels. Treatment also significantly reduced tissue levels of aortic osteocalcin, a marker of mineralization.
CONCLUSIONS
These data support a role for osteoprotegerin in the vasculature as an inhibitor of calcification and a marker, rather than a mediator, of atherosclerosis.
Topics: Animals; Aorta; Atherosclerosis; Calcinosis; Endothelium, Vascular; Mice; Mice, Knockout; Osteoprotegerin; RANK Ligand; RNA, Messenger; Receptors, LDL; Recombinant Proteins; Vascular Diseases
PubMed: 18172035
DOI: 10.1161/CIRCULATIONAHA.107.707380 -
Journal of Orthopaedic Surgery and... Nov 2023The OPG/RANKL signal pathway was important regulation mechanism of bone remodeling cycle, but the effect of osteoprotegerin (OPG) and RANKL in osteoporosis was... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The OPG/RANKL signal pathway was important regulation mechanism of bone remodeling cycle, but the effect of osteoprotegerin (OPG) and RANKL in osteoporosis was uncertain. We did a systematic review with meta-analysis to assess the association between serum OPG/RANKL and osteoporosis.
METHODS
The systematic search, data extraction, critical appraisal, and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Randomized controlled studies were searched in PubMed, OvidMedline, Embase (1946 to present). Standard mean difference (SMD), and associated credible interval (CI) were calculated using RevMan statistical software to assess the continuous data. Heterogeneity in studies was measured by I values. Subgroup analysis was performed based on different bone turnover.
RESULTS
A total of 5 randomized controlled studies met the inclusion criteria. Both OPG and RANKL had no significant differences between the osteoporosis and control group, and the statistical heterogeneity was high in meta-analysis. However, RANKL had significant differences between the osteoporosis group with low bone turnover and control group (SMD = - 1.17; 95% CI - 1.77 to 0.57; P value < 0.01) in subanalysis. Furthermore, the OPG/RANKL ratio was significant lower in the osteoporosis group than in the control group (SMD = - 0.29; 95% CI - 0.57 to - 0.02; P value < 0.05), and the statistical heterogeneity was very low (Chi = 0.20, P = 0.66, I = 0%).
CONCLUSIONS
Our meta-analysis study supported OPG and RANKL were important modulatory factors of bone formation and resorption in bone turnover, respectively. Although the serum level of both OPG and RANKL were not associated with osteoporosis, but the OPG/RANKL ratio was associated with osteoporosis. In future, standardizing the test method and unit was good to clinical application.
Topics: Humans; Osteoprotegerin; Osteoporosis; Bone Remodeling; Osteogenesis; RANK Ligand; Bone Density
PubMed: 37932757
DOI: 10.1186/s13018-023-04179-5 -
Clinical Rheumatology Oct 2017This study aimed to systemically review the evidence regarding the relationship between the circulating blood osteoprotegerin (OPG) level and rheumatoid arthritis (RA),... (Meta-Analysis)
Meta-Analysis Review
This study aimed to systemically review the evidence regarding the relationship between the circulating blood osteoprotegerin (OPG) level and rheumatoid arthritis (RA), as well as the potential influential factors. Research related to plasma/serum OPG levels in RA patients and healthy controls were gathered using PubMed, EMBASE, and The Cochrane Library database (up to Jan. 1, 2017). Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed-effects or random-effect model analysis. Heterogeneity test was performed by the Q statistic and quantified using I , and publication bias was evaluated using a funnel plot and Egger's linear regression test. After searching databases, 443 articles were obtained, and 11 studies with 710 RA patients and 561 controls were finally included. Meta-analysis revealed that, compared with the control group, the OPG level was significantly higher in the RA group (P < 0.001), with the SMD of 1.02 and 95%CI (0.20, 1.84). Subgroup analyses showed that race, disease duration, body mass index (BMI), and disease activity score based on the assessment of 28 joints (DAS28) were positively associated with OPG level in RA patients. Our meta-analysis revealed a significantly higher circulating OPG level in RA patients, and it was influenced by race, disease duration, BMI, and DAS28.
Topics: Adult; Aged; Arthritis, Rheumatoid; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Ethnicity; Female; Humans; Linear Models; Male; Middle Aged; Osteoprotegerin; Severity of Illness Index; Time Factors
PubMed: 28698901
DOI: 10.1007/s10067-017-3747-x -
Frontiers in Bioscience : a Journal and... Jan 2008Increasing experimental evidence suggests that both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its soluble decoy receptor osteoprotegerin... (Review)
Review
Increasing experimental evidence suggests that both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its soluble decoy receptor osteoprotegerin (OPG) are involved in vascular biology. In particular, emerging data indicate that recombinant soluble TRAIL may act as a molecule with potential anti-inflammatory activity in vascular physiopathology. Conversely, the presence of leukocytes expressing membrane-bound TRAIL in atherosclerotic lesions might be involved in the destabilization of atherosclerotic plaques by inducing apoptotic cell death of vascular smooth muscle cells in an inflammatory milieu. Also OPG seems to be involved in vascular homeostasis, by acting in a paracrine or autocrine manner as a survival factor for endothelial cells. However, an increased production of OPG may have a role in the development of vascular dysfunction likely by multiple potential mechanisms, not only related to its ability to neutralize TRAIL-activity but also mediated by its heparin-binding domain. In this review we have summarized and discussed both in vitro and in vivo data that suggest potential roles of TRAIL and OPG in vascular physiopathology. Further studies are needed to address how the TRAIL/OPG interaction, their reciprocal balance and/or interplay affect vascular biology in order to design innovative therapeutic strategies in vascular diseases.
Topics: Animals; Atherosclerosis; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Humans; Models, Biological; Osteoprotegerin; TNF-Related Apoptosis-Inducing Ligand; Vascular Diseases
PubMed: 17981533
DOI: 10.2741/2665 -
Circulation. Cardiovascular Genetics Feb 2017Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial...
BACKGROUND
Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity.
METHODS AND RESULTS
Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416- and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin αβ to elicit downstream focal adhesion kinase and AKT pathway activation.
CONCLUSIONS
Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease.
Topics: Animals; Arterial Pressure; Case-Control Studies; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Female; Focal Adhesion Kinase 1; Humans; Hypertension, Pulmonary; Hypoxia; Indoles; Integrin alphaVbeta3; Male; Mice, Knockout; Middle Aged; Monocrotaline; Muscle, Smooth, Vascular; Osteoprotegerin; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Pyrroles; RNA Interference; Rats, Sprague-Dawley; Severity of Illness Index; Signal Transduction; Transfection; Vascular Remodeling; Walk Test
PubMed: 28077433
DOI: 10.1161/CIRCGENETICS.116.001591 -
Oral Surgery, Oral Medicine, Oral... Mar 2022This study aimed to investigate genetic variations in the osteoprotegerin-encoding gene (TNFRSF11B) in patients with temporomandibular joint ankylosis (TMJA).
OBJECTIVE
This study aimed to investigate genetic variations in the osteoprotegerin-encoding gene (TNFRSF11B) in patients with temporomandibular joint ankylosis (TMJA).
STUDY DESIGN
The sample comprised 17 patients diagnosed with TMJA, of both sexes with ages ranging from 6 to 57 years old. TNFRSF11B mutational analysis was performed using the Sanger sequencing method with DNA extracted from oral cells, and the functional impact prediction of the variants was assessed using bioinformatic analysis.
RESULTS
Sequencing analysis identified 15 (88.23%) patients that presented at least 1 genetic variant in TNFRSF11B. The mutation rs202090603 (p.E33K) was found in 6 individuals, and rs140782326 (p.V281M), rs11573942 (p.L295), and rs1375250340 (p.I389T) were identified in 1 subject each. According to the pathogenicity potential of mutations, 3 variants were considered of low impact (rs2073618, rs202090603, and rs2228568) and 3 as disease causing (rs140782326, rs11573942, and rs1375250340). The variant rs202090603 (p.E33K) was found in the first cysteine domain with differences in the loop positions of p.E33K mutated the 3D structure of osteoprotegerin.
CONCLUSION
Two polymorphisms (rs2073618 and rs2228568) and the mutations rs202090603 (p.E33K), rs140782326 (p.V281M), rs11573942 (p.L295), and rs1375250340 (p.I389T) in the TNFRSF11B gene may be associated with TMJA.
Topics: Adolescent; Adult; Ankylosis; Child; Female; Humans; Male; Middle Aged; Mutation; Osteoprotegerin; Temporomandibular Joint; Temporomandibular Joint Disorders; Young Adult
PubMed: 34758942
DOI: 10.1016/j.oooo.2021.08.017 -
Puerto Rico Health Sciences Journal Mar 2022Periodontitis (POD) is an infectious process directed at the structures supporting the teeth. Destruction of alveolar bone is considered one of the main causes of tooth...
OBJECTIVE
Periodontitis (POD) is an infectious process directed at the structures supporting the teeth. Destruction of alveolar bone is considered one of the main causes of tooth loss in humans and is mediated by the host immune response. Osteoprotegerin (OPG), a protein that inhibits bone resorption by binding to the RANK ligand (RANKL), prevents osteoclastic differentiation. The aim of the study was to determine the plasma levels of OPG in patients with POD.
METHODS
a case-control study with forty-nine patients with POD and 49 healthy controls were included in the study. OPG levels were determined by an ELISA test in plasma samples.
RESULTS
OPG values (1.6203 ng/mL) were higher in the POD group compared with control group (1.2824 ng/mL). Among the studied groups, we detected significant differences in age, glycosylated haemoglobin (HbA1C), and plasma concentration of OPG (p < 0.05).
CONCLUSION
plasma OPG levels are associated with bone formation and destruction processes, suggesting that OPG acts in a protective manner.
Topics: Alveolar Bone Loss; Case-Control Studies; Humans; Osteoprotegerin; Periodontitis; RANK Ligand
PubMed: 35438888
DOI: No ID Found